From the Editor

Psychiatry is Neurology: White matter pathology permeates psychiatric disorders

Current Psychiatry. 2021 June;20(6):7-10 | doi:10.12788/cp.0138

References

1. Sagarwala R and Nasrallah HA. White matter pathology is shared across multiple psychiatric brain disorders: Is abnormal diffusivity a transdiagnostic biomarker for psychopathology? Biomarkers in Neuropsychiatry. 2020;2:00010. https://doi.org/10.1016/j.bionps.2019.100010
2. Pearce JMS; FRCP. The “split brain” and Roger Wolcott Sperry (1913-1994). Rev Neurol (Paris). 2019;175(4):217-220.
3. Nasrallah HA, Andreasen NC, Coffman JA, et al. A controlled magnetic resonance imaging study of corpus callosum thickness in schizophrenia. Biol Psychiatry. 1986;21(3):274-282.
4. Nasrallah HA, McChesney CM. Psychopathology of corpus callosum tumors. Biol Psychiatry. 1981;16(7):663-669.
5. Nasrallah HA. The unintegrated right cerebral hemispheric consciousness as alien intruder: a possible mechanism for Schneiderian delusions in schizophrenia. Compr Psychiatry. 1985;26(3):273-282.
6. Friston K, Brown HR, Siemerkus J, et al. The dysconnection hypothesis (2016). Schizophr Res. 2016;176(2-3):83-94.
7. Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015;161(1):102-112.
8. Benedetti F, Bollettini I. Recent findings on the role of white matter pathology in bipolar disorder. Harv Rev Psychiatry. 2014;22(6):338-341.
9. Zheng H, Bergamino M, Ford BN, et al; Tulsa 1000 Investigators. Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder. Neuropsychopharmacology. 2021;46(5):928-938.
10. Sagarwala R, Nasrallah HA. A systematic review of diffusion tensor imaging studies in drug-naïve OCD patients before and after pharmacotherapy. Ann Clin Psychiatry. 2020;32(1):42-47.
11. Lee KS, Lee SH. White matter-based structural brain network of anxiety. Adv Exp Med Biol. 2020;1191:61-70.
12. Swanson MR, Hazlett HC. White matter as a monitoring biomarker for neurodevelopmental disorder intervention studies. J Neurodev Disord. 2019;11(1):33.
13. Hampton WH, Hanik IM, Olson IR. Substance abuse and white matter: findings, limitations, and future of diffusion tensor imaging research. Drug Alcohol Depend. 2019;197:288-298.
14. Waller R, Dotterer HL, Murray L, et al. White-matter tract abnormalities and antisocial behavior: a systematic review of diffusion tensor imaging studies across development. Neuroimage Clin. 2017;14:201-215.
15. Wolf RC, Pujara MS, Motzkin JC, et al. Interpersonal traits of psychopathy linked to reduced integrity of the uncinate fasciculus. Hum Brain Mapp. 2015;36(10):4202-4209.
16. Puzzo I, Seunarine K, Sully K, et al. Altered white-matter microstructure in conduct disorder is specifically associated with elevated callous-unemotional traits. J Abnorm Child Psychol. 2018;46(7):1451-1466.
17. Finger EC, Marsh A, Blair KS, et al. Impaired functional but preserved structural connectivity in limbic white matter tracts in youth with conduct disorder or oppositional defiant disorder plus psychopathic traits. Psychiatry Res. 2012;202(3):239-244.
18. Li C, Dong M, Womer FY, et al. Transdiagnostic time-varying dysconnectivity across major psychiatric disorders. Hum Brain Mapp. 2021;42(4):1182-1196.
19. Khanbabaei M, Hughes E, Ellegood J, et al. Precocious myelination in a mouse model of autism. Transl Psychiatry. 2019;9(1):251.
20. Petratos S, Theotokis P, Kim MJ, et al. That’s a wrap! Molecular drivers governing neuronal nogo receptor-dependent myelin plasticity and integrity. Front Cell Neurosci. 2020;14:227
21. Fernandez-Enright F, Andrews JL, Newell KA, et al. Novel implications of Lingo-1 and its signaling partners in schizophrenia. Transl Psychiatry. 2014;4(1):e348. doi: 10.1038/tp.2013.121
22. Bartzokis G, Lu PH, Stewart SB, et al. In vivo evidence of differential impact of typical and atypical antipsychotics on intracortical myelin in adults with schizophrenia. Schizophr Res. 2009;113(2-3):322-331.
23. Bartzokis G, Lu PH, Amar CP, et al. Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory. Schizophr Res. 2011 Oct;132(1):35-41
24. Tishler TA, Bartzokis G, Lu PH, et al. Abnormal trajectory of intracortical myelination in schizophrenia implicates white matter in disease pathophysiology and the therapeutic mechanism of action of antipsychotics. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3(5):454-462.
25. Ren Y, Wang H, Xiao L. Improving myelin/oligodendrocyte-related dysfunction: a new mechanism of antipsychotics in the treatment of schizophrenia? Int J Neuropsychopharmacol. 2013;16(3):691-700.
26. Dietz AG, Goldman SA, Nedergaard M. Glial cells in schizophrenia: a unified hypothesis. Lancet Psychiatry. 2020;7(3):272-281.
27. Chen AT, Nasrallah HA. Neuroprotective effects of the second generation antipsychotics. Schizophr Res. 2019;208:1-7
28. Sagarwala R, Nasrallah HA. (In press.) The effect of antipsychotic medications on white matter integrity in first-episode drug naïve patients with psychosis. Asian Journal of Psychiatry.
29. Nasrallah HA. Let’s tear down the silos and reunify psychiatry and neurology. Current Psychiatry. 2013;12(8):9-10.

I then conducted a clinical study examining patients with tumors impinging on the corpus callosum, which revealed that they developed psychotic symptoms (delusions and hallucinations).⁴This study suggested that disrupting the integrity of the callosal inter-hemispheric fibers can trigger fixed false beliefs and perceptual anomalies.⁴

A ‘dysconnection’ between hemispheres

I translated those observations about the corpus callosum into a published hypothesis⁵ in which I proposed that Schneider’s First-Rank Symptoms of schizophrenia of thought insertion, thought withdrawal, and thought broadcasting—as well as delusional experiences of “external control”—may be due to a neurobiologic abnormality in the corpus callosum that disrupts the flow of ongoing bits of information transmitted from the left to the right hemisphere, and vice versa. I proposed in my model that this disruption leads to the verbal left hemisphere of a psychotic patient to describe having thoughts inserted into it from an alien source, failing to recognize that the thoughts it is receiving are being transmitted from the disconnected right hemisphere, which is no longer part of the “self.” Similarly, impulses from the right hemispheric consciousness are now perceived by the patient’s verbal left hemisphere (which talks to the examining physician) as “external control.” Thus, I postulated that an abnormal corpus callosum structure would lead to a “dysconnection” (not “disconnection”) between the 2 hemispheres, and that anomalous dysconnectivity may generate both delusions and hallucinations.⁶

Two decades later, my assumptions were vindicated when DTI was invented, enabling the measurement of WM integrity, including the corpus callosum, the largest body of WM in the brain. Table 1 defines the main parameters of WM integrity, anisotropy and diffusivity, which measure water flow inside WM fibers.

During the past 15 years, many studies have confirmed the presence of significant abnormalities in the myelinated fibers of the corpus callosum in schizophrenia, which can be considered a validation of my hypothesis that the corpus callosum becomes a dysfunctional channel of communications between the right and left hemisphere. Subsequently, DTI studies have reported a spectrum of WM pathologies in various other cerebral bundles and not only in schizophrenia, but also in other major psychiatric disorders (Table 2^7-19).

The pathophysiology of WM pathology in many psychiatric disorders may include neurodevelopmental aberrations (genetic, environmental, or both, which may alter WM structure and/or myelination), neuroinflammation, or oxidative stress (free radicals), which can cause disintegration of the vital myelin sheaths, leading to disruption of brain connectivity.^6,7 Researchers now consider the brain’s WM network dysconnectivity as generating a variety of psychiatric symptoms, including psychosis, depression, mania, anxiety, autism, aggression, impulsivity, psychopathy, and cognitive impairments.

It is not surprising that WM repair has become a therapeutic target in psychiatry and neurology. Among the strategies being investigated are inhibiting the Nogo-A signaling pathways²⁰ or modulating the Lingo-1 signaling.²¹ However, the most well-established myelin repair pathway is prolactin, a neuroprotective hormone with several beneficial effects on the brain (Table 3^22,23), including the proliferation of oligodendroglia, the main source of myelin (and the number of which declines in schizophrenia). Antipsychotics that increase prolactin have been shown to increase WM volume.^24,25 It has even been proposed that a decline in oligodendrocytes and low myelin synthesis may be one of the neurobiologic pathologies in schizophrenia.²⁶ One of the 24 neuroprotective properties of the second-generation antipsychotics (SGAs) is the restoration of WM integrity.²⁷ It’s worth noting that WM pathology has been found to be present at the onset of schizophrenia before treatment, and that SGAs have been reported to correct it.²⁸

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Psychiatry is Neurology: White matter pathology permeates psychiatric disorders

References

A ‘dysconnection’ between hemispheres

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